Paclitaxel is one of the most promising chemotherapeutic agents that has entered clinical testing in the last decade. It has shown impressive activity against ovarian and mammary carcinomas, and is currently undergoing clinical phase II-III trials against several different malignancies. The available results indicate, that the drug may be of considerable value also against lymphomas and different kinds of leukemia. The supply of the drug has been limited due to cumbersome extraction methodology, that as its exclusive starting material utilized the bark of the pacific yew tree. This shortcoming has to some extent been alleviated by the recent development of techniques to extract paclitaxel from the needles of the yew tree as well as from the bark. Technology has also been developed for the semisynthetic production of taxol from naturally available precursor substances that are in abundant supply. Although paclitaxel is now available for parenteral administration, there is only one formulation that is approved for human use, available from Bristol-Myers-Squibb (Taxol.TM.). This formulation contains 50% (v/v) alcohol, as well as an 88-fold excess of polyoxyethylated castor oil (Cremophor.RTM. EL), which has a potential for inducing serious side effects. The acute and common clinical side effects of the available paclitaxel formulation are severe: listing dyspnea, hypotension, angioedema, generalized urticaria, and most notably anaphylactoid reactions, with risk for a fatal outcome. In addition, the high Cremophor.RTM. EL concentrations facilitate the leaking of "plasticizers", i.e., chemicals used in the manufacture of disposable infusion bags and iv tubing sets into the infusate, and the (long-term) risks of patient exposure to these chemicals is unknown. This experience of severe acute side effects from the currently used drug preparation has mandated premedication with diphenhydramine, H.sub.2 -antagonists, and even corticosteroids.
There is need, therefore, for formulations of taxanes based on alternative solvent systems. This would alleviate dangerous side effects and provide a more even drug supply for both conventional dose therapy and for high dose chemotherapy using paclitaxel and related taxane compounds.